Spray-drying process

ABSTRACT

The process comprises delivering a spray solution comprising an active agent and a matrix material in an organic solvent to a spray-drying apparatus, atomizing the spray solution into droplets within the spray-drying apparatus to remove at least a portion of the organic solvent from the droplets to form a plurality of particles, and collecting the particles. The spray solution may be formed by forming a feed suspension comprising the active agent, the matrix material, and the organic solvent, wherein the feed suspension is at a temperature T1, and directing the feed suspension to a heat exchanger, thereby increasing the temperature of the feed suspension to a temperature T2, wherein T2 is greater than T1, and the spray solution is at a pressure greater than the vapor pressure of the organic solvent at T2, such that the active agent and matrix material are soluble in the organic solvent at T2.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation of application Ser. No. 13/259,082, filed Sep.22, 2011, now U.S. Pat. No. 9,724,664, which is the U.S. National Stageof International Application No. PCT/US2010/027930, filed Mar. 19, 2010,which was published in English under PCT Article 21(2), which in turnclaims the benefit of U.S. Provisional Application No. 61/164,353, filedMar. 27, 2009, each of which is incorporated herein in its entirety byreference.

BACKGROUND

A novel spray-drying process is disclosed. The process can lead tospray-dried products with improved properties, as well as increasedthroughput relative to conventional spray-drying processes.

The use of spray drying to produce powders from fluid feed stocks iswell known, with applications ranging from powdered milk to bulkchemicals and pharmaceuticals. See U.S. Pat. No. 4,187,617 and Mujumbaret al., Drying 91, pages 56-73 (1991). See also Masters, Spray DryingHandbook, pages 263-268 (4th edition, 1985). The use of spray drying toform solid amorphous dispersions of drugs or active agents andconcentration-enhancing polymers is also known. See commonly owned U.S.Pat. Nos. 6,763,607 and 6,973,741.

When it is desired to form a spray-dried product in which the drug oractive agent is amorphous, it is desirable to have the active agentfully dissolved in the spray solution when it is atomized into droplets.Specifically, when it is desired to form a spray-dried product in whichthe amorphous active agent is dispersed in one or more other materials,termed matrix material, it is generally desired to have at least a partand often all of the matrix material also dissolved in the spraysolution. In such cases, the throughput of a conventional spray-dryingprocess is often limited by the amount of active agent and matrixmaterial that can be dissolved in the spray solution. It is generallyknown that the solubility of many substances, such as active agents andmatrix materials, often increases as the temperature of the solvent isincreased. However, industry avoids using elevated temperatures whenusing organic solvents, due to the inherent dangers and safety concernswhen processing organic solvents, which are often flammable at hightemperatures. In addition, conventional spray-drying processes avoid useof elevated temperatures out of concern for the thermal stability of theactive agent and matrix material-degradation of the active agent and/orthe matrix material can lead to unwanted breakdown products in theparticles produced.

Because of this, conventional spray-drying solutions are generally keptat or near room temperature when entering the spray nozzle. This limitsthe throughput of the process due to the often low solubility of activeagents and matrix materials in the solvents used. In addition, when thesolubility of the active agent in the spray solution is low, the activeagent is often dissolved to near its solubility limit to achieve as higha throughput as possible. The spray-dried products obtained from suchsolutions are often not homogeneous. Finally, conventional spray-driedprocesses often produce products that suffer from not being homogeneousbecause the rate of solvent removal is not sufficiently fast, and broadranges of particle sizes are produced because the atomization meansproduces a wide range of droplet sizes.

U.S. Patent Application Publication No. 2008/0248114A1 describes theproduction of solid solutions containing poorly-soluble activesubstances using a spray-drying process utilizing short-term heating andrapid drying. The process avoids organic solvents by utilizing a feedstream that is an aqueous suspension of the active. The aqueoussuspension is heated to allow dissolution of the active in the spraysolution. However, this process is limited to actives that have a highsolubility in water at elevated temperature.

What is needed is a spray-drying process that results in improvedproperties of the spray-dried product, such as a higher degree ofhomogeneity and more uniform particle size, and that improves thethroughput of spray-drying equipment while spraying solutions of anactive agent and the matrix material, and provides a safe, reproducibleprocess to produce high-quality product. Such a process promises toincrease the quality and decrease manufacturing costs for spray-driedproducts.

SUMMARY

A process for increasing the throughput of a spray drier comprises (a)delivering a spray solution comprising an active agent and a matrixmaterial in an organic solvent to a spray-drying apparatus, (b)atomizing the spray solution into droplets within the spray-dryingapparatus to remove at least a portion of the organic solvent from thedroplets to form a plurality of particles, and (c) collecting theparticles. The spray solution is formed by forming a feed suspensioncomprising the active agent, the matrix material, and the organicsolvent, wherein the feed suspension is at a temperature T₁, anddirecting the feed suspension to a heat exchanger, thereby increasingthe temperature of the feed suspension to a temperature T₂, wherein (i)temperature T₂ is greater than temperature T₁, and (ii) the spraysolution is at a pressure that is greater than the vapor pressure of thesolvent at temperature T₂, such that substantially all of the activeagent in the spray solution and at least a portion of the matrixmaterial are soluble in the solvent at temperature T₂.

In one embodiment, temperature T₂ is greater than the ambient-pressureboiling point of the organic solvent.

In another embodiment, the nozzle used for atomization of the spraysolution is a pressure nozzle. In another embodiment, the nozzle usedfor atomization of the spray solution in the spray-drying apparatus is aflash nozzle. A flash nozzle utilizes a pressure drop that inducescavitation in the spray solution prior to exiting the nozzle orifice toinduce droplet formation. A sweep gas around the orifice is used toeliminate or reduce solids build-up during operation.

In another aspect, the matrix material comprises a polymer.

In still another aspect, the particles comprise a solid amorphousdispersion of the active agent and a polymer.

The disclosed processes provide one or more advantages over aconventional spray-drying process. Certain embodiments of the disclosedprocesses can increase the throughput of a spray dryer by forming aspray solution that has a higher concentration at a higher temperaturethan conventional processes. Additionally, certain embodiments of thedisclosed processes allow spray-drying solutions wherein ratio of theconcentration of active agent in the spray solution to the solubility ofthe active agent in the organic solvent at the atomization temperatureis significantly less than one, preferably less than 0.5, and even morepreferably less than 0.3. Operating in this regime generally leads tospray-dried products that are more homogeneous and more uniform. Inaddition, the disclosed processes result in rapid evaporation of theorganic solvent, and shorter times to solidification than conventionalprocesses. Furthermore, in some embodiments, the process results inimproved atomization of the spray solution relative to conventionalprocesses due to the temperature of the spray solution when it isatomized being above the boiling point of the solvent at the pressure ofthe drying chamber.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 is a schematic of a spray-drying apparatus suitable for use inperforming the process of the invention.

FIG. 2 is a schematic of a flash nozzle, suitable for use in performingthe process of the invention.

FIG. 3 is a figure showing the results of powder X-ray diffraction ofthe samples of Example 1, Control 1, and Control 2.

DETAILED DESCRIPTION

A spray-drying process for producing a composition comprising an activeagent and a matrix material is described. The spray-drying process,suitable apparatus for carrying out the process, and suitable activeagents and matrix materials are described in detail below.

Unless otherwise indicated, all numbers expressing quantities ofcomponents, molecular weights, percentages, temperatures, times, and soforth, as used in the specification or claims are to be understood asbeing modified by the term “about.” Accordingly, unless otherwiseindicated, implicitly or explicitly, the numerical parameters set forthare approximations that may depend on the desired properties soughtand/or limits of detection under standard test conditions/methods. Whendirectly and explicitly distinguishing embodiments from discussed priorart, the embodiment numbers are not approximates unless the word “about”is recited.

Spray-Drying Process

The term spray drying is used conventionally and broadly refers toprocesses involving breaking up liquid mixtures into small droplets(atomization) and rapidly removing solvent from the mixture in acontainer (drying chamber) where there is a strong driving force forevaporation of solvent from the droplets. The strong driving force forsolvent evaporation is generally provided by maintaining the partialpressure of solvent in the spray-drying apparatus well below the vaporpressure of the solvent at the temperature of the drying droplets. Thisis accomplished by (1) mixing the liquid droplets with a warm dryinggas, (2) maintaining the pressure in the spray-drying apparatus at apartial vacuum (e.g., 0.01 atm to 0.50 atm), or (3) both.

Generally, the temperature and flow rate of the drying gas is chosen sothat the droplets of spray solution are dry enough by the time theyreach the wall of the apparatus that they are essentially solid, form afine powder, and do not stick to the apparatus wall. The actual lengthof time to achieve this level of dryness depends on the size of thedroplets and the conditions at which the process is operated. Dropletsizes may range from 1 μm to 500 μm in diameter, the size beingdependent on the desired particle size of the spray dried powder. Thelarge surface-to-volume ratio of the droplets and the large drivingforce for evaporation of solvent lead to actual drying times of a fewseconds or less, and often less than 0.1 second. Solidification timesshould be less than 100 seconds, and often less than a few seconds.

Turning to the drawings, wherein the same numerals refer to likeelements, there is shown in FIG. 1 an apparatus 10 suitable forperforming embodiments of the disclosed processes. In the followingdiscussion it is assumed that the spray-drying apparatus is cylindrical.However, the dryer may take any other cross-sectional shape suitable forspray drying a spray solution, including square, rectangular, andoctagonal, among others. The spray-drying apparatus is also depicted ashaving one nozzle. However, multiple nozzles can be included in thespray-drying apparatus to achieve higher throughput of the spraysolution.

The apparatus shown in FIG. 1 includes a feed suspension tank 20, a heatexchanger 30, a drying chamber 40, a nozzle 50, and aparticle-collection means 60. In one embodiment, the process isperformed as follows. An active agent and a matrix material are combinedwith an organic solvent in the feed suspension tank 20 to form a feedsuspension. The feed suspension is at a temperature T₁, which is belowthe ambient-pressure boiling point of the organic solvent. TemperatureT₁ is also below either T_(A), the temperature at which the active agentsolubility equals the active agent concentration in the organic solvent,or T_(M), the temperature at which the matrix material solubility equalsthe matrix material concentration in the organic solvent. At least aportion of the active agent, a portion of the matrix material, or aportion of both the active agent and the matrix material are suspended,that is not dissolved, in the organic solvent. An optional mixing means22 may be used to keep the feed suspension homogeneous while processing.When the organic solvent is flammable, oxygen is normally excluded fromall parts of the drying apparatus. In particular, an inert gas, such asnitrogen, helium, argon, and the like, is often used to fill the voidspace in the feed suspension tank for safety reasons.

As used herein, the term “feed suspension” means a compositioncomprising an active agent, a matrix material, and an organic solvent,wherein at least a portion of the active agent, a portion of the matrixmaterial, or a portion of both active agent and matrix material aresuspended or not dissolved in the organic solvent. In one embodiment,the feed suspension consists essentially of an active agent, a matrixmaterial, and an organic solvent. In still another embodiment, the feedsuspension consists of an active agent, a matrix material, and anorganic solvent. In yet another embodiment, the feed suspension consistsof particles of active agent suspended in a solution of matrix materialdissolved in the organic solvent. It will be recognized that in suchfeed suspensions, a portion of the active agent and the matrix materialmay dissolve up to their solubility limits at the temperature of thefeed suspension.

As used herein, the term “organic solvent” means an organic compoundthat can be used to dissolve the active agent and the matrix material atelevated temperature. In one embodiment, the solvent is volatile, havingan ambient-pressure boiling point of 150° C. or less. In anotherembodiment, the solvent has an ambient-pressure boiling point of 100° C.or less. Suitable solvents include alcohols such as methanol, ethanol,n-propanol, isopropanol, and butanol; ketones such as acetone, methylethyl ketone and methyl isobutyl ketone; esters such as ethyl acetateand propyl acetate; and various other solvents, such as tetrahydrofuran,acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane.Lower volatility solvents such as dimethylacetamide or dimethylsulfoxidecan also be used, generally in combination with a volatile solvent.Mixtures of solvents, such as 50% methanol and 50% acetone, can also beused, as can mixtures with water. In one embodiment, the organic solventcontains less than 50 wt % water. In another embodiment, the organicsolvent contains less than 25 wt % water. In still another embodiment,the organic solvent contains less than 10 wt % water. In yet anotherembodiment, the organic solvent contains less than 5 wt % water. Inanother embodiment, the organic solvent contains essentially no water.

For convenience, the feed suspension is often maintained at near-ambienttemperatures; however, this is not a limitation of the disclosedprocesses. Generally, the temperature of the feed suspension, T₁, canrange from 0° C. to 50° C. or even higher. Temperatures of less than 0°C. may also be utilized, especially when there are stability concernsabout the active agent.

The feed suspension in the feed suspension tank 20 is delivered to apump 24, which directs the feed suspension to a heat exchanger 30. Theheat exchanger has a feed suspension inlet 26, a spray solution outlet36, a heating fluid inlet 32, and a heating fluid outlet 34. In the heatexchanger 30, the feed suspension enters through the feed suspensioninlet 26 at temperature T₁, and exits as the spray solution through thespray solution outlet 36 at temperature T₂. Spray solution temperatureT₂ is greater than feed suspension temperature T₁. To prevent unwantedvaporization/boiling of the organic solvent in the spray solution, pump24 increases the pressure of the spray solution such that the pressureof the spray solution at spray solution outlet 36 is greater than thevapor pressure of the organic solvent at temperature T₂. The temperatureof the spray solution when it enters the nozzle 50 is generally near T₂.Preferably it is within 30° C. of temperature T₂. In addition, T₂ isgreater than or equal to the lesser of T_(A) and T_(M). In oneembodiment, T₂ is greater than or equal to the greater of T_(A) andT_(M). When it is the object of the process to form a solid amorphousdispersion of the active agent and the matrix material, T₂ is greaterthan or equal to T_(A). Preferably, T₂ is at least 10° C. greater thanT_(A). In one embodiment, the spray solution temperature T₂ is greaterthan the ambient-pressure boiling point of the organic solvent.

The spray solution exiting the heat exchanger may be at any temperature,T₂, which is greater than T₁, as long as T₂ is greater than or equal tothe lesser of T_(A) and T_(M). Temperature T₂ may be at least 10° C.greater than T₁, at least 20° C. greater than T₁, at least 30° C.greater than T₁, at least 40° C. greater than T₁, or even at least 50°C. greater than T₁. In one embodiment, temperature T₂ is at least 50° C.In another embodiment, temperature T₂ is at least 70° C. In anotherembodiment, temperature T₂ is at least 80° C. In another embodiment,temperature T₂ is at least 90° C. In another embodiment, T₂ is at least100° C. In still another embodiment, T₂ is at least 120° C.

The active agent and the matrix material are both soluble in the organicsolvent at temperature T₂. By “soluble” is meant that essentially all ofthe active agent and matrix material are dissolved in the organicsolvent at temperature T₂. In the case of the active agent, the term“dissolved” has the conventional meaning, indicating that the activeagent has gone into solution. In the case of matrix materials, the term“dissolved” can take a broader definition. For some matrix materials,such as polymers, the term dissolved can mean the polymer has gone intosolution, or it can mean the polymer is dispersed or highly swollen withthe organic solvent such that it acts as if it were in solution. Incontrast, at temperature T₁, at least one of the active agent and thematrix material are present as a suspension in the organic solvent. Anysuitable technique may be used to determine if the active agent andmatrix material are soluble in the organic solvent at temperature T₂.Examples include dynamic or static light scattering analysis, turbidityanalysis, and visual observations. In one embodiment, the spray solutioncomprises the active agent and the matrix material dissolved in theorganic solvent at temperature T₂.

In one embodiment, temperature T₂ is greater than the temperature atwhich the active agent and matrix material are soluble in the organicsolvent. That is, T₂ is greater than or equal to the greater of T_(A)and T_(M). It may be desirable that temperature T₂ be much greater thanthe greater of T_(A) and T_(M). Thus, temperature T₂ may be at least 10°C. greater than the greater of T_(A) and T_(M), at least 20° C. greaterthan the greater of T_(A) and T_(M), or even at least 30° C. greaterthan the greater of T_(A) and T_(M). Spray-dried products made byembodiments of the disclosed processes are typically more uniform andhomogeneous when temperature T₂ is greater than the greater of T_(A) andT_(M).

In one embodiment, the pump 24 increases the pressure of the spraysolution to a pressure ranging from 2 atm to 400 atm. In anotherembodiment, the pressure of the spray solution as it exits the heatexchanger 30 is greater than 10 atm.

The heat exchanger 30 may be of any design wherein heat is transferredto the feed suspension resulting in an increase in temperature. In oneembodiment, the heat exchanger 30 is an indirect heat exchanger, whereina heating fluid is in contact with the feed suspension through aheat-transfer surface. Exemplary indirect heat exchangers includetube-in-tube devices and tube-in-shell devices, both well-known in theart. The heat exchanger 30 may also be a direct heat exchanger, in whicha heating fluid, such as steam, is injected directly into the feedsuspension, resulting in an increase in the temperature of the feedsuspension. In yet another embodiment, the feed suspension flows over ahot surface, such as a resistance heating element, resulting in anincrease in temperature of the feed suspension. Other heating sourcesmay also be used, such as microwaves and ultrasonic devices that canincrease the temperature of the feed suspension.

The concentration of active agent and matrix material in the spraysolution can be virtually any value. In one embodiment, theconcentration of total solids (that is, active agent and matrixmaterial) in the organic solvent is at least 0.5 wt %. The concentrationof total solids in the organic solvent may be at least 1 wt %, at least5 wt %, or even at least 10 wt % or more. In another embodiment, theconcentration of active agent in the organic solvent is at least1.25-fold the solubility of the active agent in the organic solvent attemperature T₁. The concentration of active agent in the organic solventmay be at least 1.5-fold, at least 2.0-fold, or even 2.5-fold or morethe solubility of the active agent in the organic solvent at temperatureT₁.

In one embodiment, the residence time of the feed suspension in the heatexchanger 30 is minimized so as to limit the time thesuspension/solution is exposed to elevated temperatures. The residencetime of the suspension/solution in the heat exchanger may be less than30 minutes, less than 20 minutes, less than 10 minutes, less than 5minutes, or even less than 1 minute.

The spray solution at the spray solution outlet 36 is directed to adrying chamber 40, where it enters a nozzle 50 for atomizing the spraysolution into droplets 44. The temperature of the spray solution when itenters the nozzle 50 is the spray temperature, designated as T₃. When itis desired to keep the active agent and matrix material dissolved in thespray solution, it is often desirable for T₃ to be at or near T₂.However, there are sometimes advantages to having T₃ significantly lessthan T₂. For example, degradation of the active agent may be reduced oratomization in certain nozzles may be more effective when T₃ issignificantly less than T₂. In some cases, it is even desirable for T₃to be sufficiently low that the active agent, the matrix material, orboth the active agent and the matrix material are not soluble in thesolvent. In such cases, the solution may be below the point at which thesolutes are soluble for a sufficiently short time such that all thesolutes remain in solution until the solution is atomized.Alternatively, the solution may be below the point at which the solutesare soluble for a sufficiently long time that one or more of the matrixmaterial or the active agent may precipitate or crystallize fromsolution. In one embodiment, temperature T₃ is less than 5° C. less thanT₂. In another embodiment, temperature T₃ is less than 20° C. less thanT₂. In another embodiment, temperature T₃ is less than 50° C. less thanT₂. In still another embodiment, both temperatures T₂ and T₃ are greaterthan the greater of T_(A) and T_(M). In one embodiment, temperatures T₂and T₃ are at least 5° C. greater than the greater of T_(A) and T_(M).In another embodiment, temperatures T₂ and T₃ are at least 20° C.greater than the greater of T_(A) and T_(M). In yet another embodiment,temperatures T₂ and T₃ are at least 50° C. greater than the greater ofT_(A) and T_(M).

In one embodiment, the apparatus 10 is designed such that the time thespray solution is at a temperature greater than T₃ is minimized. Thismay be accomplished by locating the spray solution outlet 36 as close aspossible to the nozzle 50. Alternatively, the size of the tubing orfluid connections between the spray solution outlet 36 and the nozzle 50may be small, minimizing the volume of spray solution and reducing thetime the spray solution is at a temperature greater than T₃. The timethe spray solution is at a temperature greater than T₃ may be less than30 minutes, less than 20 minutes, less than 10 minutes, less than 5minutes, or even less than 1 minute.

Virtually any nozzle can be used to atomize the spray solution intodroplets. The inventors have found that pressure nozzles are effectivein embodiments of the disclosed processes. In another embodiment, aflash nozzle is used, as described below.

The drying chamber 40 also has a source of heated drying gas 42 which iscombined with the droplets 44 in the drying chamber 40. In the dryingchamber 40, at least a portion of the solvent is removed from thedroplets to form a plurality of particles comprising the active agentand the matrix material. Generally, it is desired that the droplets aresufficiently dry by the time they come in contact with the dryingchamber surface that they do not stick or coat the chamber surfaces.

The particles, along with the evaporated solvent and drying gas, exitthe drying chamber at outlet 46, and are directed to aparticle-collection means 60. Suitable particle-collection means includecyclones, filters, electrostatic particle collectors, and the like. Inthe particle-collection means 60, the evaporated solvent and drying gas62 are separated from the plurality of particles 66, allowing forcollection of the particles.

The particles may be of any desired size. In one embodiment, theparticles have an average diameter ranging from 0.5 μm to 500 μm. Inanother embodiment, the particles have a diameter ranging from 0.5 μm to100 μm. In another embodiment, the particles have an average diameter ofgreater than 10 μm. In still another embodiment, the particles have anaverage diameter of greater than 20 μm. In still another embodiment, theparticles have an average diameter of greater than 30 μm. In yet anotherembodiment, the particles have a mass median aerodynamic diameterranging from 0.5 μm to 10 μm. In still another embodiment, the particleshave a mass median aerodynamic diameter ranging from 1 μm to 5 μm.

In one embodiment, the concentration of solvent remaining in theparticles when they are collected (that is, the concentration ofresidual solvent) is less than 10 wt % based on the total weight of theparticles. In another embodiment, the concentration of residual solventin the particles when they are collected is less than 5 wt %. In yetanother embodiment, the concentration of residual solvent in theparticles is less than 3 wt %. In another embodiment, a drying processsubsequent to the spray-drying process may be used to remove residualsolvent from the particles. Exemplary processes include tray drying,fluid-bed drying, vacuum drying, and the drying processes described inWO2006/079921 and WO2008/012617.

In one embodiment, nozzle 50 is a flash nozzle 50 a. There is shown inFIG. 2 a cross-sectional schematic of a flash nozzle 50 a. Flash nozzle50 a consists of a central tube 51 and an outer tube 53. Central tube 51is in fluid communication with the inflowing spray solution 55, whileouter tube 53 is in fluid communication with a sweep gas 52. The flashnozzle 50 a has an inlet end, represented by A, and an outlet end,represented by B. The spray solution 55 from the heat exchanger 30 (notshown in FIG. 2) enters central tube 51 at A. A sweep gas 52 entersouter tube 53 at A. As spray solution 55 travels through the centraltube 51 from inlet A to outlet B, the pressure decreases due to pressuredrop. Between the inlet A and outlet B, the pressure of the spraysolution 55 decreases to a value that is less than the vapor pressure ofthe solvent in the spray solution, leading to the formation of vaporbubbles of the solvent (a process known as cavitation). By the time thespray solution 55 reaches outlet B of the central tube 51, it is a fluid56 comprising droplets of spray solution and vapor-phase solvent. In oneembodiment, the central tube 51 is coated with a non-stick coating. Inanother embodiment, the outer tube 53 is coated with a non-stickcoating. In still another embodiment, the central tube 51 and the outertube 53 are coated with a non-stick coating. Non-stick coatings include,for example, polytetrafluoroethylene (PTFE) or other suitable non-stickcoatings.

The sweep gas 52 exiting through the outer tube outlet 58 is in fluidcommunication with the fluid 56 exiting through the central tube 51. Thesweep gas 52 decreases the likelihood that solid material will form atthe exit from the central tube 51 or the outer tube 53.

Active Agents

The process of the present invention is used to form a compositioncomprising an active agent. By “active agent” is meant a drug,medicament, pharmaceutical, therapeutic agent, nutraceutical,agrochemical, fertilizer, pesticide, herbicide, nutrient, or othercompound that may be desired to be formulated with a matrix material.The active agent may be a “small molecule,” generally having a molecularweight of 2000 Daltons or less. The active agent may also be a“biological active.” Biological actives include proteins, antibodies,antibody fragments, peptides, oligoneucleotides, vaccines, and variousderivatives of such materials. In one embodiment, the active agent is asmall molecule. In another embodiment, the active agent is a biologicalactive. In still another embodiment, the active agent is a mixture of asmall molecule and a biological active. In yet another embodiment, thecompositions made by certain of the disclosed processes comprise two ormore active agents.

The active agent may be highly water soluble, sparingly water soluble,or poorly water soluble. In one embodiment, the active agent is “poorlywater soluble,” meaning that the active agent has a solubility in water(over the pH range of 6.5 to 7.5 at 25° C.) of less than 5 mg/mL. Theactive agent may have an even lower aqueous solubility, such as lessthan about 1 mg/mL, less than about 0.1 mg/mL, and even less than about0.01 mg/mL.

Matrix Materials

The disclosed processes are used to form compositions comprising amatrix material. Matrix materials suitable for use in the compositionsformed by the disclosed methods should be inert, in the sense that theydo not chemically react with the active agent in an adverse manner. Thematrix material can be neutral or ionizable. In one embodiment, thecomposition includes two or more matrix materials.

Exemplary matrix materials include polysaccharides. Polysaccharides canbe underivatized, such as cellulose, starch, dextran, pullulan, dextrin,maltodextrin, glycogen, inulin, fructan, mannan, chitin, polydextrose,fleximer (a ring-opened form of dextran), and oligosaccharides. Often,derivatives and substituted versions of the polysaccharides arepreferred. Examples of such polysaccharide derivatives include ester-and ether-linked derivatives. Included in this class are celluloseethers, cellulose esters, and cellulose derivatives that have both esterand ether substituents. Specific examples include cellulose acetate,ethyl cellulose, hydroxypropyl methyl cellulose and hydroxyethylcellulose. Starch derivatives include starch acetate and carboxymethylstarch. Also included are synthetic matrix materials, such aspolyacrylates and polymethacrylates, vinyl matrix materials,polyethylenes, polyoxyethylenes, polypropylenes, polyamides, polyesters,polycarbonates, and derivatives and substituted versions thereof;copolymers of various types, including random and block copolymers;other matrix materials such as lactose, trehalose, sucrose, fructose,maltose, dextrose, xylitol, sorbitol, glycine, amino acids, citric acid,phospholipids, bile salts; and mixtures thereof.

In one embodiment, the matrix material is amphiphilic, meaning that thematrix material has hydrophobic and hydrophilic portions. In anotherembodiment, the matrix material is ionizable.

In yet another embodiment, the matrix material comprises a polymer.Appropriate matrix polymers include polyvinylpyrrolidone, vinylacetate/vinylpyrrolidone copolymers, vinyl alcohol, vinyl acetate/vinylalcohol copolymers, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, carboxymethylcellulose, carboxymethyl ethylcellulose, hydroxypropyl methylcelluloseacetate succinate, cellulose acetate phthalate and cellulose acetatetrimellitate. In still another embodiment, the matrix material comprisesan ionizable cellulosic polymer. In yet another embodiment, the matrixmaterial comprises an amphiphilic, ionizable polymer.

In one embodiment, the matrix material is biodegradable, meaning thatthe matrix material will degrade over time. By “degrade” is meant thatin a use environment, the matrix material is broken down into smallerspecies that can be absorbed, metabolized, or otherwise eliminated orremoved from the environment of use. This degradation can occur throughenzymatic, hydrolytic, oxidative, or other reaction, as is well known inthe art, or by degrading the matrix material into aqueous solublespecies that can readily be removed from the environment of use.

Compositions

In one embodiment, the composition made by the disclosed processes is inthe form of a solid amorphous dispersion of the active agent and thematrix material.

In another embodiment, the particles comprise a solid amorphousdispersion of the active agent and matrix material consistingessentially of amorphous active agent molecularly dispersed throughoutthe matrix material. In this embodiment, the solid dispersion may beconsidered a “solid solution” of active agent and matrix material. Theterm “solid solution” includes both thermodynamically stable solidsolutions in which the active agent is completely dissolved in thematrix material, as well as homogeneous materials consisting ofamorphous active agent molecularly dispersed throughout the matrixmaterial in amounts greater than the solubility of the active agent inthe matrix material. A dispersion is considered a “solid solution” whenit displays a single glass-transition temperature when analyzed bydifferential scanning calorimetry (DSC). In one embodiment, theparticles have at least one Tg due to the amorphous character of thematrix material. In another embodiment, at least 90 wt % of the activeagent in the particles is amorphous. In yet another embodiment, theactive agent is amorphous and molecularly dispersed in a portion of oneor more of the matrix materials, while the remaining portion of thematrix materials is present as a separate phase. This separate phasematrix material may be amorphous, crystalline, or a mixture of bothamorphous and crystalline.

In another embodiment the particles comprise the active agent incrystalline form, which is homogeneously or substantially homogeneouslydistributed in the matrix material. In still another embodiment, theparticles comprise the active agent in amorphous or non-crystallineform, which is homogeneously distributed in the matrix material matrix.In yet another embodiment, the particles comprise a mixture of activeagent in crystalline and amorphous forms homogeneously distributed inthe matrix material.

In still another embodiment, the particles comprise a mixture ofactive-agent-rich domains and matrix material-rich domains. The activeagent in the domains may be amorphous, crystalline, or a mixture ofamorphous and crystalline.

In yet another embodiment, the compositions comprise a third componentin addition to the active agent and the matrix material. This thirdcomponent may be any compound or mixture of compounds that facilitatesthe intended use of the disclosed compositions. Exemplary thirdcomponents include, but are not limited to, matrix materials, surfaceactive agents, wetting agents, diluents, fillers, bulking agents,disintegrants, flavors, fragrances, buffering agents, and/or othercomponents known in the art.

Without further elaboration, it is believed that one of ordinary skillin the art can, using the foregoing description, utilize the presentinvention to its fullest extent. Therefore, the following specificembodiments are to be construed as merely illustrative and notrestrictive of the scope of the invention. Those of ordinary skill inthe art will understand that variations of the conditions and processesof the following examples can be used.

EXAMPLES

Active Agent 1 was S-(fluoromethyl)6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate,17-propionate, also known as fluticasone propionate, having thestructure:

Active Agent 1 has a solubility of 0.4 μg/mL in pH 7.4 buffer, and a LogP value of 3.7. The Tg of amorphous Active Agent 1 was determined by DSCto be 84° C. The room temperature (20° C. to 30° C.) solubility ofActive Agent 1 in methanol is 0.3 wt %.

Example 1

A spray-dried dispersion was made using an apparatus similar to thatshown in FIG. 1. A feed suspension was prepared by mixing 3 gm of ActiveAgent 1 and 9 gm of the MG grade of hydroxypropyl methylcelluloseacetate succinate (HPMCAS-MG, AQOAT-MG available from Shin Etsu, Tokyo,Japan) with 88 gm of a methanol solvent. The HPMCAS-MG dissolved in thesolvent, while the active agent remained in suspension. The feedsuspension was maintained at ambient temperature, 20° C. to 30° C., withstirring in a pressure pot to prevent settling of the particles ofActive Agent 1. The total solids content of the feed suspension was 12wt %.

The feed suspension in the pressure pot was pressurized to 245 psig anddirected at a rate of 26 gm/min to a tube-in-shell heat exchanger.Heating fluid at 160° C. was circulated in a countercurrent mannerthrough the heat exchanger. The spray solution exiting the heatexchanger was at a temperature, T₂, of 120° C., and all of the activeagent and matrix material were dissolved in the spray solution. Theaverage residence time of the spray solution in the heat exchanger wasless than 60 seconds. The total time the spray solution was at atemperature of 120° C. was less than 80 seconds. Thus, the elapsed timefrom the time the spray solution exited the heat exchanger to the timeit exited the pressure nozzle was 20 seconds. The temperature of thenozzle was 120° C.

The spray solution was delivered to the spray-drying chamber where itwas atomized using a Schlick 2.0 pressure nozzle (Düsen-Schlick GmbH ofUntersiemau, Germany). The spray solution was atomized into dropletswithin the spray-drying chamber, while simultaneously mixing thedroplets with a nitrogen drying gas which was introduced to the dryingchamber at a temperature of 140° C. and at a flow rate of 520 gm/min,resulting in the formation of solid particles.

The solid particles, along with the evaporated solvent and the dryinggas, were directed to a cyclone separator, where the solid particleswere collected. The particles were subsequently dried in a vacuumchamber at 0.15 atm for 2 to 3 hours to remove residual methanol fromthe particles.

The resulting particles had 25 wt % Active Agent 1 in HPMCAS-MG.

Control 1

As a control, a 25 wt % Active Agent 1 in HPMCAS-MG composition was madeusing a conventional ambient-temperature spray-drying process. ForControl 1, a feed solution was formed by dissolving 0.45 gm of ActiveAgent 1 and 1.35 gm of HPMCAS-MG in 179.7 gm methanol. Both the activeagent and the matrix material completely dissolved in the methanol atambient temperature. The total solids content of this solution was 1.0wt %.

This solution was spray dried using the same apparatus as described forExample 1, except that the heat exchanger was bypassed, such that thespray solution was not heated prior to atomization. All other operatingvariables were nominally the same as described in Example 1.

Control 2

As a second control, a feed suspension similar to that formed forExample 1 was prepared and then spray dried without heating the spraysolution. The feed suspension consisted of 2.25 gm of Active Agent 1,6.75 gm of HPMCAS-MG, and 66 gm of methanol, resulting in a feedsuspension containing 12 wt % solids. Because the feed was a suspensionrather than a solution, a two-fluid nozzle was used (manufactured bySpray Systems, Wheaton, Ill.) to avoid clogging.

The feed suspension was spray dried using the same apparatus asdescribed for Example 1, except that the heat exchanger was bypassed,such that the spray solution was not heated prior to atomization, and atwo-fluid nozzle was used for atomization of the feed. All otheroperating variables were nominally the same as described in Example 1.

Analysis of Compositions from Examples 1, Control 1, and Control 2

Samples of the compositions of Example 1, Control 1, and Control 2 wereanalyzed by powder X-ray diffraction using an AXS D8 Advance PXRDmeasuring device (Bruker, Inc. of Madison, Wis.). Samples (approximately100 mg) were packed in Lucite sample cups fitted with Si(511) plates asthe bottom of the cup to give no background signal. Samples were spun inthe φ plane at a rate of 30 rpm to minimize crystal orientation effects.The x-ray source (KCu_(α), λ=1.54 Å) was operated at a voltage of 45 kVand a current of 40 mA. Data for each sample were collected over aperiod of 27 minutes in continuous detector scan mode at a scan speed of1.8 seconds/step and a step size of 0.04°/step. Diffractograms werecollected over the 2θ range of 4° to 40°.

FIG. 3 shows the results of this analysis. The composition of Example 1,made using a concentrated feed suspension and a heat exchanger toincrease the feed temperature according to the disclosed processes,showed an amorphous halo, indicating the active agent in the compositionwas amorphous. Likewise, the composition of Control 1, made using aconventional spray-drying process using a dilute spray solution ofactive agent and matrix material dissolved in a solvent at ambienttemperature, also showed only an amorphous halo. However, thecomposition of Control 2, made using a concentrated feed suspension butnot heated, showed a large number of well-defined peaks, indicating thepresence of crystalline active agent in the composition.

This analysis shows that the compositions of Example 1 and Control 1 hadsimilar properties. However, because the spray solution for Example 1contained 12 wt % solids, while the spray solution for Control 1 onlycontained 1 wt % solids, certain embodiments of the disclosed processes(Example 1) had a throughput that was 12-fold greater than that of theconventional spray-drying process.

Example 2

A spray-dried dispersion is made using an apparatus similar to thatshown in FIG. 1 using the procedures outlined in Example 1, except thatthe flash nozzle of FIG. 2 is used. The resulting particles consist of25 wt % Active Agent 1 in HPMCAS.

An embodiment of the disclosed spray-drying processes comprisesdelivering a spray solution comprising an active agent and a matrixmaterial in an organic solvent to a spray-drying apparatus, atomizingsaid spray solution into droplets within said spray-drying apparatus viaa nozzle to remove at least a portion of the organic solvent from saiddroplets to form a plurality of particles, wherein said spray solutionis delivered to said nozzle at a temperature T₃, and collecting saidparticles, wherein said particles comprise said active agent and saidmatrix material, and wherein said spray solution is formed by forming afeed suspension comprising said active agent, said matrix material andsaid organic solvent, wherein said feed suspension is at a temperatureT₁, and directing said feed suspension to a heat exchanger, therebyincreasing the temperature of said feed suspension to a temperature T₂,wherein temperature T₂ is greater than temperature T₁, and said spraysolution is at a pressure that is greater than the vapor pressure ofsaid solvent at temperature T₂, such that said active agent and saidmatrix material are soluble in said solvent at temperature T₂. In oneembodiment, said temperature T₂ is greater than the ambient-pressureboiling point of said solvent.

In either of the above embodiments, said active agent and said matrixmaterial may be soluble in said solvent at temperature T₃. In any or allof the above embodiments, said spray solution may be atomized using aflash nozzle.

In any or all of the above embodiments, said temperature T₂ may be atleast 100° C. In any or all of the above embodiments, said spraysolution may be at temperature T₂ for less than 10 minutes.Alternatively, said spray solution may be at temperature T₂ for lessthan 5 minutes.

In any or all of the above embodiments, said organic solvent is selectedfrom methanol, ethanol, n-propanol, isopropanol, butanol acetone, methylethyl ketone, methyl isobutyl ketone, ethyl acetate, propyl acetate,tetrahydrofuran, acetonitrile, methylene chloride, toluene,1,1,1-trichloroethane, and mixtures thereof. In certain embodiments,said organic solvent is selected from the group consisting of methanol,ethanol, n-propanol, isopropanol, butanol acetone, methyl ethyl ketone,methyl isobutyl ketone, ethyl acetate, propyl acetate, tetrahydrofuran,acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, andmixtures thereof. In any or all of the above embodiments, said organicsolvent may contain less than 50 wt % water.

In any or all of the above embodiments, said particles may have a massmedian aerodynamic diameter ranging from 0.5 μm to 10 μm. In any or allof the above embodiments, said particles may have an average diameter ofgreater than 10 μm.

In any or all of the above embodiments, said matrix material maycomprise a polymer. In some embodiments, said particles comprise a solidamorphous dispersion of said active agent in said polymer.

Also disclosed are embodiments of products made by any or all of theabove processes. In some embodiments, the product comprises a solidamorphous dispersion of said active agent and said polymer.

An embodiment of a process for producing a composition comprises forminga feed suspension comprising an active agent, a matrix material and anorganic solvent, wherein said feed suspension is at a temperature T₁,forming a spray solution by directing said feed suspension to a heatexchanger, thereby increasing the temperature of said feed suspension toa temperature T₂, wherein temperature T₂ is greater than temperature T₁,said spray solution is at a pressure that is greater than the vaporpressure of said solvent at temperature T₂, and said active agent andsaid matrix material are soluble in said solvent at temperature T₂,directing said spray solution to a spray-drying apparatus, saidspray-drying apparatus comprising a drying chamber, a nozzle foratomizing said spray solution into droplets, and a source of heateddrying gas for removing at least a portion of said organic solvent fromsaid droplets, atomizing said spray solution into droplets in saiddrying chamber by said nozzle, wherein the spray solution is deliveredto said nozzle at a temperature T₃, contacting said droplets with saidheated drying gas to remove at least a portion of said organic solventfrom said droplets to form a plurality of particles comprising saidactive agent and said matrix material, and collecting said particles. Insome embodiments, said temperature T₂ is greater than theambient-pressure boiling point of said solvent.

In either of the above embodiments, said active agent and said matrixmaterial may be soluble in said solvent at temperature T₃.Alternatively, said active agent or said matrix material may not besoluble in said solvent at temperature T₃.

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention in the use of such terms andexpressions of excluding equivalents of the features shown and describedor portions thereof, it being recognized that the scope of the inventionis defined and limited only by the claims which follow.

What is claimed is:
 1. A spray-drying process, comprising: (a) forming afeed suspension in a tank at a temperature T₁, the feed suspensioncomprising an active agent, a matrix material, and an organic solvent,wherein the active agent is suspended in the organic solvent, andwherein the organic solvent is methanol, ethanol, n-propanol,isopropanol, butanol, acetone, methyl ethyl ketone, methyl isobutylketone, ethyl acetate, propyl acetate, tetrahydrofuran, acetonitrile,methylene chloride, toluene, 1,1,1-trichloroethane, or any mixturethereof, and contains less than 10 wt % water; (b) flowing the feedsuspension from the tank through a flow-through heat exchanger locateddownstream of and separate from the tank and upstream of a spray dryingapparatus, the flow-through heat exchanger comprising a feed suspensioninlet and a spray solution outlet to form a spray solution, wherein thefeed suspension entering the feed suspension inlet is at the temperatureT₁, wherein the temperature T₁ is below the ambient-pressure boilingpoint of the organic solvent and the matrix material is dissolved in theorganic solvent at the temperature T₁, and the spray solution at thespray solution outlet is at a temperature T₂ and at a pressure that isgreater than the vapor pressure of the organic solvent at thetemperature T₂, such that the active agent and the matrix material aresoluble in the organic solvent at the temperature T₂, wherein T₂>T₁, (c)directing the spray solution to the spray-drying apparatus via a nozzlepositioned proximate the spray solution outlet of the flow-through heatexchanger, wherein the spray solution is delivered to the nozzle at atemperature T₃, wherein the temperature T₃ is less than or equal to thetemperature T₂; and (d) atomizing the spray solution into dropletswithin the spray-drying apparatus through the nozzle to remove at leasta portion of the organic solvent from the droplets to form a pluralityof particles having an average diameter ranging from 0.5 μm to 500 μm,wherein the particles comprise a homogeneous solid amorphous dispersionof the active agent and the matrix material, wherein the spray solutionis at the temperature T₂ for less than 5 minutes.
 2. The process ofclaim 1 wherein the organic solvent contains no water and the feedsuspension comprises active agent particles suspended in a solution ofthe matrix material and the organic solvent.
 3. The process of claim 1wherein the temperature T₁ is up to 50° C.
 4. The process of claim 1wherein the temperature T₁ is ambient temperature.
 5. The process ofclaim 1 wherein the spray solution is at the temperature T₂ for lessthan 80 seconds.
 6. The process of claim 1 wherein the active agent andthe matrix material are soluble in the organic solvent at thetemperature T₃.
 7. The process of claim 1 wherein the temperature T₃ isless than the temperature T₂.
 8. The process of claim 1 wherein the feedsuspension has a residence time in the flow-through heat exchanger ofless than one minute.
 9. The process of claim 1 wherein the organicsolvent contains no water.
 10. The process of claim 1 wherein theflow-through heat exchanger is a tube-in-tube device, a tube-in-shelldevice, a heat exchanger comprising a hot surface over which the feedsuspension flows, a microwave device, or an ultrasonic device.
 11. Theprocess of claim 1 wherein the active agent has a concentration in thespray solution that is at least 1.25-fold the solubility of the activeagent in the organic solvent at the temperature T₁.
 12. The process ofclaim 1, further comprising flowing the feed suspension from the tankthrough a pump which directs the feed suspension into the feedsuspension inlet of the flow-through heat exchanger and increases thepressure of the spray solution such that the pressure of the spraysolution at the spray solution outlet is greater than the vapor pressureof the organic solvent at the temperature T₂.
 13. The process of claim 1wherein the temperature T₂ is at least 10° C. greater than T_(A) whereT_(A) is the temperature at which solubility of the active agent in theorganic solvent equals the active agent concentration in the organicsolvent.
 14. The process of claim 1 wherein the particles have anaverage diameter ranging from 0.5 μm to 100 μm.
 15. The process of claim1 wherein the matrix material comprises a polymer.
 16. The process ofclaim 15 wherein the particles comprise a solid amorphous dispersion ofthe active agent in the polymer.
 17. The process of claim 1 wherein theplurality of particles comprise the active agent and the matrixmaterial, wherein the active agent has a solubility in water at 25° C.of less than 5 mg/mL.
 18. The process of claim 1 wherein thespray-drying apparatus comprises (i) a drying chamber, (ii) the nozzle,and (iii) a source of heated drying gas for removing at least a portionof the organic solvent from the droplets, and wherein the step ofatomizing the spray solution into the droplets further comprisescontacting the droplets with the heated drying gas to remove at least aportion of the organic solvent from the droplets to form the pluralityof particles.